title: MicroRNA-146b improves intestinal injury in mouse colitis by activating nuclear factor-κB and improving epithelial barrier function.
abstract: BACKGROUND
  The precise role of microRNAs in inflammatory disease is not clear. The present study investigated the effect of microRNA (miR-146b) with respect to improving intestinal inflammation.
  
  
  METHODS
  The microRNA profile in interleukin-10 deficient mice was examined using microRNA arrays and miR-146b was selected for the subsequent experiments. The expression vectors containing either the whole sequence of miR-146b or small interfering RNA for miR-146b were intraperitoneally administered to the dextran sodium sulfate (DSS)-induced colitis mouse. The expression levels of inflammation-related mediators were examined by the reverse transcriptase-polymerase chain reaction and western blotting analysis. Intestinal barrier function was evaluated by an ex vivo mannitol flux study.
  
  
  RESULTS
  The overexpression of miR-146b activated the NF-κB pathway, improved epithelial barrier function, relieved intestinal inflammation in the DSS-induced colitis mice, and improved the survival rate of mice with lethal colitis. Furthermore, this amelioration of intestinal inflammation by miR-146b was negated by the inhibitor for the NF-κB pathway. The overexpression of miR-146b decreased the expression of siah2, which has a target sequence for miR-146b, and promoted the ubiquitination of TRAF proteins. This suggests that the up-regulation of NF-κB by miR-146b was mediated by inhibition of the ubiquitination of TRAF proteins upstream of NF-κB.
  
  
  CONCLUSIONS
  miR-146b improves intestinal inflammation by up-regulating NF-κB as a result of the decreased expression of siah2, which ubiquitinates TRAF proteins. Modulation of the miR-146b expression is a potentially useful therapy for the treatment of intestinal inflammation via activation of the NF-κB pathway.
authors.affiliation: Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
authors.forename: Toshie
authors.initials: T
authors.lastname: Nata
authors.forename: Mikihiro
authors.initials: M
authors.lastname: Fujiya
authors.forename: Nobohiro
authors.initials: N
authors.lastname: Ueno
authors.forename: Kentaro
authors.initials: K
authors.lastname: Moriichi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Konishi
authors.forename: Hiroki
authors.initials: H
authors.lastname: Tanabe
authors.forename: Takaaki
authors.initials: T
authors.lastname: Ohtake
authors.forename: Katsuya
authors.initials: K
authors.lastname: Ikuta
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kohgo
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D015153:Blotting, Western; D003092:Colitis / Q000401:mortality / Q000628:therapy*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D000893:Anti-Inflammatory Agents; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; D016328:NF-kappa B; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; C533102:Siah2 protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: gene therapy; inflammatory bowel disease (IBD)